Ignored Avenues in Alpha-Synuclein Associated Proteopathy

Alpha-Synuclein (aSyn) is a 14 kDa pre-synaptic protein predominantly expressed in various regions of brain comprising neocortex, hippocampus, striatum, thalamus and cerebellum. aSyn aggregates have special neuropathologic relevance for comprehending Parkinson's disease (PD) and other synucleopathies due to the presence of aSyn aggregates in brain of patients suffering from these diseases. Direct relationship between PD and various single nuclear polymorphisms of aSyn further displays an inherent significance of mutated aSyn in increasing the risk for developing PD. So far, various theories have been emerged to explain aSyn mediated neuronal cell toxicity seen in patients with PD, including interaction of aSyn aggregates with biomolecules, vesicle dystrafficking, augmented oxidative stress, mitochondrial dysfunction, and disruption of synaptic function. Despite the advances in understanding of PD pathophysiology, current available treatments are still aiming at giving symptomatic relief. Lately, PD vaccines against aSyn aggregates are also being considered. However, various other avenues for e. g. post-translational and conformational modifications of aSyn, effect of cellular small molecules such as polyamines and osmolytes on aSyn aggregation, still remain unexplored and we believe that therapeutics directed at these ignored targets will surface as a successful combinational therapy for PD. Additionally, understanding mechanisms behind the interplay between PD and other health conditions, such as Gaucher's disease, Cardiovascular disorders, Hypertension, Homocystinuria, Type-II Diabetes, and Cancer are also speculated to provide great insight for novel therapeutic interventions. In the current review, we have precisely discussed all these ignored avenues with their possible clinical implications. Link between PD and other associated diseases has also been extensively reviewed.